A Pathology-based Case Series of Influenza- and COVID-19–associated Pulmonary Aspergillosis: The Proof Is in the Tissue

Abstract

Rationale Invasive pulmonary aspergillosis has emerged as a frequent coinfection in severe coronavirus disease (COVID-19), similarly to influenza, yet the clinical invasiveness is more debated. Objectives We investigated the invasive nature of pulmonary aspergillosis in histology specimens of influenza and COVID-19 ICU fatalities in a tertiary care center. Methods In this monocentric, descriptive, retrospective case series, we included adult ICU patients with PCR-proven influenza/COVID-19 respiratory failure who underwent postmortem examination and/or tracheobronchial biopsy during ICU admission from September 2009 until June 2021. Diagnosis of probable/proven viral-associated pulmonary aspergillosis (VAPA) was made based on the Intensive Care Medicine influenza-associated pulmonary aspergillosis and the European Confederation of Medical Mycology (ECMM) and the International Society for Human and Animal Mycology (ISHAM) COVID-19–associated pulmonary aspergillosis consensus criteria. All respiratory tissues were independently reviewed by two experienced pathologists. Measurements and Main Results In the 44 patients of the autopsy-verified cohort, 6 proven influenza-associated and 6 proven COVID-19–associated pulmonary aspergillosis diagnoses were identified. Fungal disease was identified as a missed diagnosis upon autopsy in 8% of proven cases ( n = 1/12), yet it was most frequently found as confirmation of a probable antemortem diagnosis ( n = 11/21, 52%) despite receiving antifungal treatment. Bronchoalveolar lavage galactomannan testing showed the highest sensitivity for VAPA diagnosis. Among both viral entities, an impeded fungal growth was the predominant histologic pattern of pulmonary aspergillosis. Fungal tracheobronchitis was histologically indistinguishable in influenza ( n = 3) and COVID-19 ( n = 3) cases, yet macroscopically more extensive at bronchoscopy in influenza setting. Conclusions A proven invasive pulmonary aspergillosis diagnosis was found regularly and with a similar histological pattern in influenza and in COVID-19 ICU case fatalities. Our findings highlight an important need for VAPA awareness, with an emphasis on mycological bronchoscopic work-up.

COVID-19 associated pulmonary aspergillosis in critically-ill patients: a prospective multicenter study in the era of Delta and Omicron variants

“…The diagnostic criteria for these co-infections combine clinical, radiological, mycological, and histological criteria [ 4 ]. A recent autopsy study on patients infected with influenza and COVID-19 confirmed the invasive nature of the infection and the similarity of histological lesions observed in both IAPA and CAPA cases [ 5 ]. A multicenter French study conducted during the first wave revealed that 15% of critically ill patients with COVID-19 requiring invasive mechanical ventilation (IMV) fulfilled the diagnostic criteria for CAPA, which was also associated with poor outcomes [ 1 ].…”

“…Thus, the prognostic relevance of CAPA per se could be questioned: it might be considered a simple severity indicator rather than a truly invasive super-infection. A recent pathology-based studies has highlighted the invasive nature of CAPA [ 5 ], thereby supporting systematic CAPA screening of intubated patients and specific antifungal treatment.…”

Acute Invasive Pulmonary Aspergillosis: Clinical Presentation and Treatment

“…ICU physicians do not always consider the possibility of IPA in patients without classic host risk factors. 30 However, autopsy studies show that IPA remains one of the most common missed diagnoses among patients admitted to a medical ICU 31 32 33 34 : in one autopsy study on 893 ICU patients, only 40% of the IA cases diagnosed at autopsy had been recognized ante-mortem. 34 Although classical host risk factors might not always be present, most patients do have underlying comorbidities: in a prospective cohort study of 297 ICU patients with IA, only 5% had no underlying disease.…”

Microbiological Diagnosis of Pulmonary Aspergillus Infections

“…Autopsy studies show that diagnosis of IPA is still often missed, demonstrating the persisting limitations of our diagnostic tests and approaches. 3 4 5 6 Even more challenging is the diagnosis of fungal coinfections. Coinfections with Aspergillus and Mucorales are more common than previously thought.…”